Vertical transmission of HIV-1 is rapidly becoming a major threat to child health worldwide. HIV+ pregnant women have a 20-30% chance of passing the virus to their newborns. Recent evidence indicates that a majority of infants becomes infected late in gestation or intrapartum. Neonatal infection during birth makes HIV entry through mucous membranes likely. To date, no prophylactic strategy has proven effective in preventing vertical HIV transmission. In our prior work, we have created a primate model with a very high rate of congenital infection with the simian immunodeficiency virus (SIV) by inoculating the pathogenic SIVmac251 into the amniotic fluid which is being swallowed by the fetus. In another important development, attenuated SIV has been shown to be the most effective vaccine against pathogenic SIV in adult rhesus monkeys. The overall goal of this proposal is to use attenuated SIV (nef-, vpr-, NRE-) to vaccinate neonatal rhesus monkeys against mucosal challenge with pathogenic Sly. The Specific Aims are to: 1. Evaluate the safety of attenuated SIV in rhesus monkey (Macaca mulatta) fetuses. Groups of 2 pregnant females will undergo ultrasound- guided 'amniotic fluid inoculation with attenuated SIV in the late 3rd trimester. The offspring will be followed prospectively for viremia and disease, if any. Virus target cells and specific antiviral immune responses will be evaluated, with special emphasis on mucosal immune responses in the GI tract. 2. Infect newborn M. mulatta orally with cell-free pathogenic SIV or SIV+ cells. To titrate the infectious dose, groups of 2 newborns will be given various doses of SIV. Virus target cells in the GI tract as well as SIV- induced mucosal pathology and mucosal immune responses will be determined. The animals will be followed for viremia and disease prospectively. 3. Test immunoprophylaxis with attenuated SIV against neonatal challenge with orally administered cell-free SIV. Groups of 5 M. mulatta fetuses will be inoculated with attenuated SIV shortly before birth and challenged orally at birth. The nature of specific anti-SlV immune responses correlating with protection will be analyzed. 4. Test immunoprophylaxis with attenuated SIV against neonatal challenge with orally administered SIV-infected maternal cells. The significance of the proposed work lies in the systematic evaluation of a vaccine strategy in newborns that has been found to yield the most impressive protection against challenge with pathogenic SIV to date in adult rhesus monkeys. The identification of immune responses correlating with protection will be of great significance in designing prophylactic strategies against vertical HIV transmission.